Preoperative anxiety is a subjective feeling of worry, tension,
apprehension and nervousness. In children, it is attributed to
separation from parents. [1] It largely affects the smoothness of
induction, emergence from anaesthesia and also the psychological and
emotional state of children in the remote future. [2] A smooth
transition from an awake state to surgical anaesthesia in children
becomes a challenge for all anaesthesiologists. Eliminating or
minimising stress provides a smooth atraumatic induction of anaesthesia.
Preoperative preparation programs, parental presence during induction
and premedication with drugs are methods to allay the anxiety of the
children in the perioperative period. [3]

Among the various routes of premedication, intranasal route has
come into practice from early nineties.4,5 It is relatively a quick,
painless with a high bioavailability. Most commonly used drug for
premedication is Midazolam. Dexmedetomidine, an [alpha]2 agonist, is now
becoming popular because of its excellent sedative, anxiolytic,
sympatholytic and analgesic properties. (6,7,8)

This study was conducted to compare the effects of Dexmedetomidine
and Midazolam administered intranasally for premedication in children
undergoing elective surgery under general anaesthesia.

MATERIALS AND METHODS

This study was conducted in Thanjavur Medical College Hospital from
August 2011 to October 2013. 43 was the estimated sample size in each
group. According to a study by Meenakshi Sundaram AL et al, (9) at
induction of anaesthesia, 24.7% and 67.4% of the children from groups M
and D respectively were satisfactorily sedated with an allocation ratio
of 1, Alpha = 0.01 and Beta = 0.10. Finally, a total of 100 children
scheduled for elective surgeries under General Anaesthesia were
included, 50 in each group. Children meeting the following selection
criteria were included in the study. Block randomisation technique was
used to allocate the children to midazolam and dexmedetomidine group.
Blocks of varying sizes ranging from 2-6 used for block randomisation.
Approval from Institutional Ethical Committee was obtained.

Inclusion Criteria

1. Children of both sexes aged 5-12 Yrs.,

2. Belonging to ASA I and II,

3. Weighing <30 kg,

4. Undergoing elective surgery under GA.

Exclusion Criteria

1. Known allergy or Hypersensitivity to Dexmedetomidine or
Midazolam,

2. Organ dysfunction,

3. Cardiac arrhythmia,

4. Congenital heart disease,

5. Mental retardation,

6. Patient refusal,

7. H/o snoring or sleep apnoea,

8. Polyps and infections of nasal cavity.

The Children were Divided into Two Groups

Group IN-D (n = 50)-Intranasal Dexmedetomidine.

Group IN-M (n = 50)-Intranasal Midazolam.

Children were kept nil per oral for 8 hours. Informed written
consent was obtained from the parents. Children were randomly assigned
to one of two groups. Baseline heart rate, systolic blood pressure and
SPO2 were recorded.

Group IN-D received 1 [micro]g/kg of intranasal dexmedetomidine and
Group IN-M received 0.2 mg/kg of intranasal midazolam 60 minutes before
induction.

The study drugs were prepared by an independent person using the
intravenous preparations of dexmedetomidine (100 [micro]g/kg) and
midazolam (5 mg/mL). Intranasal medication was prepared in a 2-ml
syringe and 0.9% saline was added to make a final volume of 1.5 mL. The
medication was administered in preoperative room in the presence of one
parent (Preferably mother). The drug was dripped into the nostrils with
the child in the recumbent position. Patients and the observer were
blinded to the drug being administered.

Continuous heart rate and SPO2 monitoring done. Desaturation was
managed with O2 supplementation through nasal mask. After 60 minutes the
child was shifted to the operating table.

Sedation status was assessed during parental separation with a
6--point sedation scale Modified from the Observer Assessment of
Alertness and Sedation scale.

6--Appears alert and awake, responds readily to name.

5--Appears asleep, responds readily to name spoken in normal tone.

4--Lethargic response to name spoken in normal tone.

3--Respond only after name called loudly or repeatedly.

2--Responds only to mild prodding or shaking.

1--Does not respond to mild prodding or shaking.

Sedation score from 1-4 was considered satisfactory while score
from 5-6 was considered unsatisfactory.

Behaviour score during induction was assessed on the operating
table by a 4-point scale-

4--Crying or resisting.

3--Anxious and could not be reassured.

2--Anxious but could be reassured.

1--Calm and co-operative.

Behaviour score of 1 or 2 was considered satisfactory while 3 or 4
was considered unsatisfactory.

The acceptance of IV cannulation in the forearm of the child was
graded as

Grade 1--Calm, co-operative, asleep-Good.

Grade 2--Co-operative with reassurance-Moderate.

Grade 3--Combative, crying-Poor.

Glycopyrrolate 10 [micro]g/kg, ondansetron 0.15 mg/kg were given IV
preoxygenation done with 100% O2 for 3 minutes with a scented facemask.
Acceptance of facemask by the child was graded with the same grading as
that of the acceptance of IV cannulation.

With standard monitoring, General Anaesthesia was administered.
Recovery was good and the children were shifted to postoperative ward.

Statistical Analysis

The collected data were analysed by using GraphPad Instat 3.06
software according to variables for chi square test and student's
t-test. The results are obtained in the form of range, mean and standard
deviation. The probability value 'p' of less than 0.05 was
considered statistically significant.

RESULTS

Patient's demographic data including age, sex and weight
between two groups were comparable (table 1). The age distribution was
in the range of 5-12 years in both the groups. The mean age of group
IN-D is 9.04 and group IN-M is 8.80. The mean weight of group IN-D was
23.36 kg and that of group IN-M was 23 kg. The p value was 0.692
(>0.05) was statistically not significant.

The mean sedation score in group IN-D was 3.24 and in group IN-M
was 4.32. Sedation score at parental separation was satisfactory in 88%
(44 children) of the group IN-D and in 60% (30 children) of the group
IN-M. It was found to be unsatisfactory in 12% (6 children) of the group
IN-D and in 40% (20 children) of the IN-M group. The 'p' value
was 0.030 (<0.05) which was statistically significant.

The behaviour score in the operating table was satisfactory in 88%
(44 children) of group IN-D and 92% (46 children) of group IN-M. It was
unsatisfactory in 12% (6 children) of group IN-D and in 8% (4 children)
in group IN-M. The 'p' value was 0.738 (> 0.05) which was
statistically not significant.

The table 3 shows the distribution of acceptance of IV cannulation
between two groups. The grading was good in 36%, moderate in 56% and
poor in 8% of the children in both the groups.

Acceptance of facemask was good in 68% of the children in group
IN-D and in 60% of the children in group IN-M. Only two children (4%) in
group IN-D had a poor acceptance of facemask ('p' = 0.401).

Continuous heart rate and SPO2 monitored, none of the children in
either of the groups attained significant bradycardia and desaturation
(<95%). No subjective adverse effects were observed in group IN-D.
Three children complained of nasal irritation and child had paradoxical
excitation in group IN-M following drug administration. These parameters
were not statistically analysed as our study was not designed to
investigate these parameters.

DISCUSSION

Selecting appropriate premedication in safe yet effective doses is
a primary responsibility of an anaesthesiologist. Facilitating an
anxiety free separation and a smooth induction are the primary goals of
premedicant drug administration. Analgesia, amnesia, and prevention of
physiologic stress are other beneficial effects of pharmacological
intervention. The main drawback of premedication particularly in
children is that the process of administering the medication may
actually increase anxiety. A child's major fear associated with
hospitalisation is fear from needles and injections. Thus, a
non-invasive route is generally preferred.

Various routes for premedication in children have been formulated
keeping in mind the specific problems of the paediatric age group.
Intranasal route is a rapid and effective way of administering
premedication in children. Among the non-invasive routes, it has gained
importance in recent decades. It provides a direct route into the
systemic circulation for drugs that easily cross mucous membranes.
Importantly the first bypass metabolism is circumvented and the
bioavailability is better than other routes. For many intranasal
medications, the rates of absorption and plasma concentrations are
comparable to intravenous administration and are typically better than
subcutaneous or intramuscular routes. Oral route is poorly accepted and
rectal route is less ideal especially for older children.

Alpha--2 agonists are assuming greater importance as anaesthetic
adjuvants and analgesics. [10,11] Dexmedetomidine is a highly selective,
specific and potent alpha--2 adrenoceptor. It was introduced in United
States and had been in clinical practice since 1999. Sedative--hypnotic
effects are produced by the action on alpha--2 receptors in the locus
coeruleus. Analgesic effect is produced by its action on alpha--2
receptors within the locus coeruleus and within the spinal cord. Despite
effective sedation there is limited respiratory depression. Following
intranasal administration, 1 [micro]g/kg has an onset time of 45 minutes
with a peak effect at 60-105 minutes in healthy adults. Bioavailability
of intranasal dexmedetomidine is 65% (35-93%). [12] Whereas the
sedation, anterograde amnesia and anticonvulsant properties of midazolam
are mediated via alpha 1 GABA receptors. These receptors are found in
highest densities in the olfactory bulb, cerebral cortex, cerebellum,
hippocampus, substantia nigra and inferior colliculus.

Among the large percentage of paediatric patients, anaesthesia
induction was known to be the anxiety provoking part. Awake intravenous
cannulation and parental separation were more vulnerable points. So this
study was designed to compare the efficacy of intranasal dexmedetomidine
and midazolam with respect to sedation status at parental separation,
behaviour level inside the operating room, acceptance of IV cannulation
and acceptance of facemask during induction.

Several studies had used intranasal midazolam and the possibility
of neurotoxicity occurred only after chronic administration through
intrathecal route. [13] TimoIirola et al [12] showed intranasal
dexmedetomidine does not produce local effects on nasal mucosa like
mucosal irritation, ulceration, inflammation and bleeding.
Pradiptabhakta et al [14] in their study concluded that intranasal
midazolam in a dose of 0.2 mg/kg was as effective as 0.3 mg/kg in
producing anxiolysis and sedation. Yuen et al [15] observed that 1
[micro]g/kg dexmedetomidine produced significant and satisfactory
sedation at parental separation and at induction. Aynur et al [16]
compared the efficacy of 1 [micro]g/kg of dexmedetomidine and 0.2 mg/kg
of midazolam administered intranasally as premedication agents in
children between 2-9 years.

The sedation produced by dexmedetomidine significantly differs when
compared with other drugs that act through GABA systems. [15] Among the
50 children, 22 children (88%) in group IN-D and 15 children (60%) in
group IN-M attained a significant and satisfactory sedation status at
parental separation at 60 minutes (p = 0.030). While Aynur akin et al
[16] showed that 79.9% in group D and 95.5% in group M attained
satisfactory sedation (45 minutes). The peak effect of intranasal
midazolam is 10-15 minutes and duration of action is 30-60 minutes. In
this study, the sedation status was assessed at 60 minutes, so only 60%
in group IN-M was found with satisfactory sedation. The mean sedation
score in group IN-D was 3.24 [+ or -] 0.959 and in group IN-M was 4.32
[+ or -] 0.748 (p = 0.001).

The behaviour level of the children was assessed with a four point
scale. 88% of children in group IN-D and 92% in group IN-M attained
satisfactory behaviour score (score 1 or 2). None of the children in
either groups had worst and unsatisfactory behaviour (score 4). 3
children (12%) in group IN-D and 2 (8%) in group IN-M had score 3
(Anxious, not reassured). Yuen et al [15] in their study also showed
that children in groups M, D-0.5 and D-1 premedicated with midazolam
(0.5 mg/kg) and dexmedetomidine (0.5 and 1 [micro]g/kg) had comparable
behaviour level. There was a tendency of the children in groups D-0.5
and D-1 having unsatisfactory behaviour after shifting to operating
room. But still there were no statistically significant differences when
compared to group M.

Children usually have an aversion for needles. If acceptance of the
IV cannulation is good enough, it indirectly counterchecks the sedation
status and behaviour level. The children in both groups IN-D and IN-M
had similar acceptance of IV cannulation (p = 1.000).

The acceptance of facemask was good (score 1) in 68% of the
children in group IN-D and in 60% of the children in group IN-M. It was
found to be moderate (score 2) in 28% of the children in group IN-D and
in 40% of the children in group IN-M. 2 children (4%) in group IN-D had
a poor (score 3) acceptance of facemask (p = 0.401).

Limitations of the Study

This study was conducted entirely in the preoperative period, the
intraoperative and the postoperative effects were not evaluated.

In summary, we found that intranasal administration of
dexmedetomidine 1 [micro]g/kg for premedication in children undergoing
elective surgery provides significant and satisfactory sedation
('p' = 0.030). However, intranasal midazolam was as effective
as dexmedetomidine in providing satisfactory behaviour level inside the
operating room. Both the intranasal premedicants were equally effective
in providing satisfactory conditions for acceptance of IV cannulation
and acceptance of facemask during induction.

CONCLUSION

Intranasal premedication allows an effective and predictable
sedation in children. Both midazolam and dexmedetomidine produce a good
level of sedation, behaviour and acceptable levels for IV cannulation
and face mask acceptance during induction. But the quality of sedation
is significantly better in dexmedetomidine group.